The GIT1 and GIT2 proteins are GTPase-activating proteins for the Arf small GTP-binding proteins. Together with the alpha-PIX and beta-PIX proteins (themselves guanine nucleotide exchange factors for Rho family small GTP-binding proteins), GIT proteins form an oligomeric signaling scaffolding complex. GIT/PIX complexes have been shown to bind to a variety of protein kinases as well as other signaling proteins, and to localize to several distinct cellular locations through interaction with specific partners. Although GIT and PIX proteins have been implicated in a wide variety of cellular processes, including vesicle trafficking, focal adhesion dynamics and synapse formation, little is known of the physiological functions of these proteins. To address this, we created GIT1-KO and GIT2-KO knockout mouse lines, with inactivated GIT1 or GIT2 genes, and subjected them to unbiased behavioral screens. One striking difference we noted between GIT1-KO and GIT2-KO mice is that GIT1-KO mice are scarcely affected by fearful stimuli, while GIT2-KO mice greatly over- respond to invoked fear. Since we have previously shown that both GIT1 and GIT2 function as Arf GAPs, form similar GIT/PIX complexes, and are widely expressed throughout the brain, the mechanistic reasons for such dissimilar behavioral effects remain unknown. The main hypothesis underlying this study is that GIT2 is an important regulator of learned fear behavior, and lack of GIT2 predisposes mice to a syndrome with high similarity to post-traumatic stress disorder (PTSD). The major aims of this project are to define the effect of SSRI treatment on fear behavior in GIT2-KO mice, to define the hormonal/neurochemical responses to stress in GIT2-KO mice, and to identify cellular signaling mechanisms through which GIT2 affects fear responses in mice. A more complete understanding of altered fear responses in GIT2-KO mice will allow validation of GIT2- KO mice as an animal model for human PTSD. PUBLIC HEALTH RELEVANCE: The genetic and/or neurochemical bases for the inability to overcome trauma-induced fear in PTSD remains mostly unknown, and treatment options are limited. Mice deficient in the GIT2 protein overrespond to conditioned fear in a manner reminiscent of human PTSD. A deeper understanding of how GIT2 functions to regulate anxiety and the extinction of fear may provide insights into human fear and anxiety disorders such as PTSD.